Development of substrate‐selective γ‐secretase cleavage inhibitors has been a long‐standing goal, especially in the AD field, but previously reported Notch‐sparing GSIs such Avagacestat, when tested in direct cleavage, assays often do not show substrate selectivity between NOTCH1 and APP (Crump et al, 2012). Here, NOTCH1 is linked to Alzheimer disease.